The present invention relates to benzopyrans and benzoxepines which can be used in the treatment of dyslipidaemias, atherosclerosis and diabetes, to pharmaceutical compositions comprising them and to processes allowing the preparation of these compounds. compounds in the preparation of medicaments intended for the treatment of dyslipidaemias, atherosclerosis and diabetes.
Cardiovascular disease remains, in most countries, one of the main diseases and the main cause of mortality. Approximately a third of men develop a major cardiovascular disease before the age of 60, women exhibiting a lower risk (ratio of 1 to 10). This disease becomes more prevalent with age (after the age of 65, women become just as vulnerable to cardiovascular diseases as men). Vascular diseases, such as coronary disease, strokes, restenosis and peripheral vascular disease, remain the main cause of mortality and handicap across the world.
While diet and lifestyle can accelerate the development of cardiovascular diseases, a genetic predisposition leading to dyslipidaemias is a significant factor in strokes and deaths.
The development of atherosclerosis seems to be related mainly to dyslipidaemia, which means abnormal levels of lipoproteins in the blood plasma. This dysfunction is particularly evident in coronary disease, diabetes and obesity.
The concept intended to explain the development of atherosclerosis was mainly focused on the metabolism of cholesterol and on the metabolism of triglycerides.
However, since the studies by Randle et al. (lancet, 1963, 785-789), a novel concept has been proposed: a glucose-fatty acid cycle or Randle cycle, which describes the regulation of the equilibrium between the metabolism of lipids, in terms of triglycerides and cholesterol, and the oxidation of glucose. According to this concept, the Inventors have developed a novel programme having the aim of finding new compounds which act simultaneously on the metabolism of lipids and the metabolism of glucose.
Fibrates are well-known therapeutic agents with a mechanism of action via the xe2x80x9cPeroxisome Proliferator Activated Receptorsxe2x80x9d. These receptors are the main regulators of the metabolism of lipids in the liver (PPARxcex1 isoform). In the last ten years, thiazolidinediones have been described as powerful hypoglycaemic agents in animals and man. It has been reported that thiazolidinediones are powerful selective activators of another isoform of PPARs: the various PPARxcex3 (Lehmann et al., J. Biol. Chem. 1995, 270, 12953-12956).
The Inventors have discovered a new class of compounds which are powerful activators of the PPARxcex1 and PPARxcex3 isoforms. Due to this activity, these compounds exhibit a significant hypolipidaemic and hypoglycaemic effect.
The compounds of the invention correspond to the formula (I) below: 
in which:
X represents O or S;
A represents either the divalent radical xe2x80x94(CH2)sxe2x80x94COxe2x80x94(CH2)txe2x80x94 or the divalent radical xe2x80x94(CH2)sxe2x80x94CR3R4xe2x80x94(CH2)txe2x80x94
in which radicals s=t=0 or else one of s and t has the value 0 and the other has the value 1;
R4 represents a hydrogen atom or a (C1-C15)alkyl group;
R1 and R2 independently represent the Z chain defined below; a hydrogen atom; a (C1-C18)alkyl group; a (C2-C18)alkenyl group; a (C2-C18)alkynyl group; a (C6-C10)aryl group optionally substituted by a halogen atom, by an optionally halogenated (C1-C5)alkyl group or by an optionally halogenated (C1-C5)alkoxy group; or a mono- or bicyclic (C4-C12)heteroaryl group comprising one or more heteroatoms chosen from O, N and S which is optionally substituted by a halogen atom, by an optionally, halogenated (C1-C5)alkyl group or by an optionally halogenated (C1-C5)alkoxy group;
R3 takes any one of meanings given above for R1 and R2, with the exception of the Z chain; or else
R3 and R4 together form a (C2-C6)alkylene chain optionally substituted by a halogen atom or by optionally halogenated (C1-C5)alkoxy;
R is chosen from a halogen atom; a cyano group; a nitro group; a carboxy group; an optionally halogenated (C1-C18)alkoxycarbonyl group; an Raxe2x80x94COxe2x80x94NHxe2x80x94 or RaRbNxe2x80x94COxe2x80x94 group [in which Ra and Rb independently represent optionally halogenated (C1-C18)alkyl; a hydrogen atom; (C6-C10)aryl or (C6-C10)aryl(C1-C5)alkyl (where the aryl parts are optionally substituted by a halogen atom, by an optionally halogenated (C1-C5)alkyl group or by an optionally halogenated (C1-C5)alkoxy group); (C3-C12)cycloalkyl optionally substituted by a halogen atom, by an optionally halogenated (C1-C5)alkyl group or by an optionally halogenated (C1-C5)alkoxy group]; an optionally halogenated (C1-C18)alkyl group; optionally halogenated (C1-C18)alkoxy; and (C6-C10)aryl, (C6-C10)aryl(C1-C5)alkyl, (C6-C10)aryloxy, (C3-C12)cycloalkyl, (C3-C12)cycloalkenyl, (C3-C12)cycloalkyloxy, (C3-C12)cycloalkenyloxy or (C6-C10)aryloxycarbonyl in which the aryl, cycloalkyl and cycloalkenyl parts are optionally substituted by a halogen atom, by optionally halogenated (C1-C5)alkyl or by optionally halogenated (C1-C5)alkoxy;
p represents 0, 1, 2, 3 or 4;
Z represents the radical: 
where
n is 1 or 2;
the Rxe2x80x2 groups independently represent a hydrogen atom; a (C1-C5)alkyl group; a (C6-C10)aryl group optionally substituted by a halogen atom, by an optionally halogenated (C1-C5)alkyl group or by optionally halogenated (C1-C5)alkoxy; or a mono- or bicyclic (C4-C12)heteroaryl group comprising one or more heteroatoms chosen from O, N and S which is optionally substituted by a halogen atom, by an optionally halogenated (C1-C5)alkyl group or by an optionally halogenated (C1-C5)alkoxy group;
Y represents xe2x80x94OH; (C1-C5)alkoxy; or the xe2x80x94NRcRd group (in which Rc and Rd independently represent a hydrogen atom; (C1-C5)alkyl; (C3-C8)cycloalkyl optionally substituted by a halogen atom, by optionally halogenated (C1-C5)alkyl or by optionally halogenated (C1-C5)alkoxy; (C6-C10)aryl optionally substituted by a halogen atom, by optionally halogenated (C1-C5)alkyl or by optionally halogenated (C1-C5)alkoxy; it being understood that one and one alone from R1 and R2 represents the Z chain.
The invention is also targeted, depending on the functional groups present in the molecule, at the salts of these compounds with pharmaceutically acceptable acids or bases.
When the compound of formula (I) comprises an acidic functional group, for example a carboxyl functional group, the latter can form a salt with an inorganic or organic base.
Mention may be made, as example [sic] of salts with organic or inorganic bases, of the salts formed with metals and in particular alkali, alkaline earth and transition metals (such as sodium, potassium calcium, magnesium or aluminium) or with bases, such as ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine), or with basic amino acids or with osamines (such as meglumine) or with aminoalcohols (such as 3-aminobutanol and 2-aminoethanol).
When the compound of formula (I) comprises a basic functional group, for example a nitrogen atom, the latter can form a salt with an organic or inorganic acid.
The salts with organic or inorganic acids are, for example, the hydrochloride, hydrobromide, sulphate, hydrogensulphase, dihydrogenphosphate, maleate, fumarate, 2-naphthalenesulphonate and para-toluene-sulphonate salts.
The invention also covers the salts which make possible a suitable separation or a suitable crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example tartaric acid, dibenzoyltartaric acid, mandelic acid or camphorsulphonic acid.
The formula (I) encompasses all the types of geometric isomers and stereoisomers of the compounds of formula (I).
According to the invention, the term xe2x80x9calkylxe2x80x9d denotes a linear or branched hydrocarbon-comprising radical, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
When the alkyl group is substituted by one or more halogen atoms, it is preferable for it to represent perfluoroalkyl and in particular penafluoroethyl or trifluoromethyl.
The term xe2x80x9calkoxyxe2x80x9d denotes an alkyl group as defined above bonded to an oxygen atom. Examples thereof are the methoxy, ethoxy, isopropyloxy, butoxy and hexyloxy radicals.
The term xe2x80x9calkylene groupxe2x80x9d is understood to mean linear or branched alkylene groups, that is to say bivalent radicals which are linear or branched bivalent alkyl chains.
The term xe2x80x9ccycloalkylxe2x80x9d denotes saturated hydrocarbon-comprising groups which can be mono- or polycyclic and comprise from 3 to 12 carbon atoms, preferably from 3 to 8. Preference is more particularly given to monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
The term xe2x80x9ccycloalkenylxe2x80x9d is understood to mean, according to the invention, a cycloalkyl group exhibiting one or more double bonds.
The term xe2x80x9chalogenxe2x80x9d is understood to mean a fluorine, chlorine, bromine or iodine atom.
The term xe2x80x9carylxe2x80x9d represents a mono- or bicyclic aromatic hydrocarbon-comprising group comprising 6 to 10 carbon atoms, such as phenyl or naphthyl.
The term xe2x80x9cmono- or bicyclic heteroarylxe2x80x9d denotes monocyclic or bicyclic aromatic groups comprising one or more endocyclic heteratoms. Examples thereof are the furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolyl, quinolizinyl, iqoquinolyl [sic], cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, pteridinyl and benzoxepinyl groups.
Preferred heteroaryls comprise from 4 to 10 carbon atoms and from 1 to 2 heteroatoms.
The alkenyl and alkynyl groups can comprise more than one unsaturation.
The alkenyl groups comprise unsaturations of ethylenic type and the alkynyl groups comprise unsaturations of acetylenic type.
The (C6-C10)aryl, (C3-C8)cycloalkyl, heteroaryl and cycloalkenyl groups are optionally substituted. The expression xe2x80x9coptionally substituted by a halogen atom, by an optionally halogenated (C1-C15)alkyl group or by an optionally halogenated (C1-C5)alkoxy groupxe2x80x9d indicates that the said aryl, cycloalkyl, heteroaryl and cycloalkenyl groups are optionally substituted by one or more substituents chosen from:
halogen atoms;
alkyl groups optionally substituted by one or more halogen atoms; and
alkoxy groups optionally substituted by one or more halogen atoms.
In the same way, the alkylene chain, when it is substituted, can comprise one or more identical or different substituents chosen from halogen atoms and optionally halogenated alkoxy groups.
The expression xe2x80x9coptionally halogenatedxe2x80x9d means, in the context of the invention, optionally substituted by one or more halogen atoms.
In the context of the present invention, the term xe2x80x9cbenzoxepinexe2x80x9d has been used to denote the benzo[b]oxepine structure of formula: 
According to the invention, preference is given to the compounds in which A represents the radical:
xe2x80x94(CH2)sxe2x80x94CR3R4xe2x80x94(CH2)txe2x80x94
where s, t, R3 and R4 are as defined above for the formula (I).
Another preferred group of compounds of formula (I) is composed:
xe2x80xa2of the compounds in which:
X represents O;
A represents xe2x80x94CR3R4xe2x80x94 or xe2x80x94CH2xe2x80x94CR3R4xe2x80x94 in which the unsubstituted methylene group is bonded to X;
R1 and R2 independently represent Z; H; (C1-C15)alkyl; (C1-C15)alkenyl [six]; or phenyl optionally substituted by (C1-C5)alkyl, (C1-C5)alkoxy, a halogen atom or xe2x80x94CF3;
R3 takes any one of the meanings given above for R1 and R2, with the exception of Z;
R is chosen from (C1-C9)alkyl; (C1-C5)alkoxy; phenyl or phenylcarbonyl optionally substituted by a halogen atom, (C1-C5)alkyl, (C1-C5)alkoxy, xe2x80x94CF3 or xe2x80x94OCF3; a halogen atom; xe2x80x94CF3 and xe2x80x94OCF3;
Z represents the radical: 
where
n represents 1;
Rxe2x80x2 represents (C1-C5)alkyl.
Preference is given, among these compounds, to those in which:
X represents O;
A represents xe2x80x94CR3R4xe2x80x94;
Z represents 
xe2x80xa2or alternatively those in which:
X represents O;
A represents xe2x80x94CH2xe2x80x94CR3R4xe2x80x94 in which the unsubstituted methylene group is bonded to X;
R1 and R2 independently represent Z, a hydrogen atom or (C1-C5)alkyl;
R3 takes any one of the meanings given above for R1 and R2, with the exception of Z;
Z represents 
Rxe2x80x2 represents methyl or phenyl.
Preferred meanings of Y are:
xe2x80x94OH
xe2x80x94(C1-C5)alkoxy; and
xe2x80x94NRcRd where Rc and Rd are as defined above for the formula (I).
Very preferably, Y represents xe2x80x94OH or xe2x80x94(C1-C5)alkoxy.
Likewise, it is preferable for p to have the value 0, 1 or 2.
According to a particularly advantageous embodiment of the invention, the compounds of the groups which are preferred defined above are such that p and Y take one of these meanings.
Mention may be made, as example [sic] of preferred compounds, of the following compounds:
xe2x80x94(2E, 4E)-5-(2-pentyl-2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2Z, 4E)-5-(2-pentyl-2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(2,2-dimethyl-6-methoxy-2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(2,2-dimethyl-2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2Z, 4E)-5-(2,2-dimethyl-2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-[2-(non-6-enyl)-2H-1-benzopyran-3-yl]-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(4-phenyl-2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(6-nonyl-2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(6-phenyl-2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(2-nonyl-2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(4-methyl-2H-1-benzoypyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2Z, 4E)-5-(2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(2-undecanyl-2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(2-phenyl-2H-1-benzopyran-3-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(5-methyl-2,3-dihydrobenzoxepin-4-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid; and [sic]
xe2x80x94(2E, 4E)-5-(2,3-dihydrobenzoxepin-4-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl)-3-phenylpenta-2,4-dienoic acid;
xe2x80x94(2Z, 4E)-5-(3,3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl)-3-phenylpenta-2,4-dienoic acid;
xe2x80x94(2Z, 4E)-5-(3,3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-7,8-dimethoxy-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-2,3-dihydro-7-(para-chlorobenzoyl)benzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-7-chloro-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-7,8-dichloro-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-7-bromo-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-7-fluoro-8-chloro-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-7-fluoro-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-7-trifluoromethyl-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-7-phenyl-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3,7-trimethyl-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(3,3-dimethyl-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
xe2x80x94(2E, 4E)-5-(9-methoxy-3,3-dimethyl-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid;
and their pharmaceutically acceptable esters, such as their ethyl esters.
FR 2,698,873 discloses compounds of formula: 
which are powerful activators of the potassium channels of the cell membrane.
According to this document, none of the R1 to R7 substituents represents the Z chain as defined in the invention.
U.S. Pat. No. 5,391,569 relates to benzopyrans of formula: 
of use in the treatment of osteoporosis and inflammations. These compounds differ from the compounds of the invention in that the alkenyl chain comprises three double bonds, whereas, according to the invention, the Z chain comprises either two or four double bonds.
It should be noted that the hypolipidaemic and hypoglycaemic activity of the compounds of the invention is unrelated to the activity of the compounds disclosed in the documents U.S. Pat. No. 5,391,569 and FR 2,698,273.
The compounds of formula (I) can be prepared by using one of the following Processes A or B, which processes form another subject-matter of the invention.
Process A makes possible the preparation of the compounds of formula (I) in which n represents 1.
This process comprises the stages composed of:
(a1) preparing an ylide
xe2x80xa2 either by reaction of a base with a phosphonate of formula: 
in which
Rxe2x80x2 is as defined in Claim 1 [sic];
T1 and T2 independently represent (C1-C5)alkyl; and
Y represents (C1-C5)alkoxy,
xe2x80xa2 or by reaction of a base with a phosphonium salt of formula (IIb); 
in which
Rxe2x80x2 is as defined in Claim 1 [sic];
T3, T4 and T5 independently represent (C1-C5)alkyl or (C6-C10)aryl optionally substituted by (C1-C5)alkyl;
Y represents (C1-C5)alkoxy; and
hal represents a halogen atom;
(b1) reacting the ylide obtained in Stage (a1) with an aldehyde of formula: 
in which
R, p, X and A are as defined in Claim 1 [sic];
one and one alone of Rxe2x80x21 and Rxe2x80x22 represents xe2x80x94CHO and the other takes one of the meanings given in Claim 1 [sic] for R1 and R2, with the exception of the Z chain, so as to obtain a compound of formula (I) in which n represents 1 and Y represents (C1-C5)alkoxy;
(c1) if appropriate, converting the ester obtained in Stage (b1) above in acidic or basic medium into the corresponding carboxylic acid of formula (I) in which Y represents OH;
(d1) if appropriate, reacting the carboxylic acid functional group of the compound of formula (I) resulting from Stage (c1) with an amine of formula HNRcRd in which Rc and Rd are as defined in Claim 1 [sic], optionally after activation of the carboxyl functional group, so as to prepare the corresponding compound of formula (I) in which Y represents xe2x80x94NRcRd.
The reaction employed in Stage (b1) is either a Wittig reaction or a Horner-Emmons or Wadsworth-Emmons reaction.
It results in the preparation of a reactive ylide.
When the ylide is prepared from a phosphonium salt (compound IIb), the reaction employed is a Wittig reaction.
When the ylide is prepared from a phosphonate (compound IIa), the reaction employed is a Horner-Emmons or Wadsworth-Emmons reaction.
In Stage a1 [sic], the ylide is prepared by reaction of a base either with a compound IIa [sic] or with a compound IIb [sic]. The base used must be sufficiently strong to detach the proton at the position xcex1 to the phosphorus.
The base is generally chosen from an alkali metal hydride, an alkali metal carbonate, an alkali metal amide, a (C1-C10)alkyllithium and an alkali metal alkoxide.
Mention may be made, by way of example [sic], of sodium hydride, potassium carbonate, n-butyllithium, potassium tert-butoxide, a [sic] lithium amide or a [sic] sodium amide.
In the context of the invention, sodium hydride and potassium tert-butoxide are preferred as base.
The reaction of the base with the compound (IIa) OR (IIb) is carried out in solution, preferably in an aprotic solvent and more particularly in a solvent capable of dissolving the phosphonate (IIa) or the phosphonium salt (IIb) respectively.
Appropriate solvents are aprotic solvents, such as, for example and non-limitingly, aromatic hydrocarbons (such as benzene and toluene), ethers (such as diethyl ether, dioxane or tetrahydrofuran) and their mixtures.
The choice of the solvent depends in particular on the type of ylide (compounds IIa or IIb).
According to a preferred embodiment of the invention, stage (b2) [sic] of reaction of the aldehyde with the ylide is carried out by addition of the aldehyde (III) to the crude reaction mixture resulting from Stage (a1), that is to say without isolation of the intermediate ylide.
Thus, it is desirable for the solvent of Stage (a1) also to be capable of dissolving the aldehyde (III). However, another embodiment of the invention comprises the addition of a solution of the aldehyde (III) in a solvent to the crude reaction mixture resulting from Stage (a1). Under these conditions, it is not necessary to select, in Stage (a1), a solvent capable of dissolving the compound (III).
The temperature at which Stage (a1) is carried out depends on the acidity of the compound (IIa) or (IIb) respectively, that is to say on the ease with which the proton at the position xcex1 to the phosphorus can be detached. It goes without saying that the type of base used directly influences the choice of the reaction temperature. Thus, the stronger the base, the lower the reaction temperature. When the base used is n-butyllithium, a temperature of between xe2x88x9280xc2x0 C. and xe2x88x9240xc2x0 C., preferably between xe2x88x9280xc2x0 C. and xe2x88x9270xc2x0 C., is generally desirable. In this case, the solvent is chosen so as to make possible such severe reaction conditions; ethers are very particularly well suited.
When the base is an alkali metal alkoxide, a temperature of between 10 and 100xc2x0 C. is generally suitable. If, furthermore, this base is reacted with a phosphonate (IIa), a temperature of between 15 and 70xc2x0 C. is generally sufficient.
When the base used is an alkali metal hydride, the temperature is generally between xe2x88x9210xc2x0 C. and 50xc2x0 C. If, furthermore, this base is reacted with a phosphonate (IIa), a temperature of between xe2x88x925xc2x0 C. and 30xc2x0 C. is generally sufficient.
A stoichiometric amount of the base is needed in Stage (a1) to detach the proton at the position xcex1 to the phosphorus on the compound (IIa) or (IIb) respectively. Nevertheless, it is possible to use a very slight excess of base, so that the reaction for the formation of the ylide is complete. Thus, the molar ratio of the base to the compound (IIa) or (IIb) respectively is maintained between 1 and 1.2, preferably between 1 and 1.1, better still between 1 and 1.05.
The concentration of the compound (IIa) or (IIb) respectively in the reaction mixture is not critical according to the invention. The concentration generally varies between 0.01 mol/l and 10 mol/l, preferably between 0.1 and/ 1 mol/l.
In Stage (b1), the aldehyde (III) is reacted with the ylide resulting from Stage (a1).
The aldehyde (III) is advantageously added to the crude reaction mixture resulting from Stage (a1).
The aldehyde (III) can be added as is to the reaction mixture or else in solution in a solvent, preferably an aprotic solvent.
Mention may be made, as preferred solvents, of solvents of aromatic hydrocarbon, ether, N-dimethylformamide [sic], dimethyl sulphoxide, N-methylpyrrolidone or P[N(CH3)2]3 type and their mixtures which were cited above.
Whatever the operating procedure, it is preferable for the concentration of aldehyde (III) in the reacting mixture to vary between 6xc3x9710xe2x88x923 and 0.6 mol/l, preferably between 0.01 and 0.7 mol/l.
The temperature at which the ylide reacts with the aldehyde (III) depends on the respective reactivity of the two reactants.
It should be noted that the ylide prepared from the phosphonate (IIa) is more reactive than the ylide prepared from the compound (IIb). Thus, Process A, involving the implementation of a reaction of Horner-Emmons type with the use of the phosphonate (IIa), is particularly advantageous.
Generally, a temperature of between xe2x88x9210xc2x0 C. and 50xc2x0 C. is appropriate for the reaction of the ylide with the aldehyde (III), a temperature of between xe2x88x925xc2x0 C. and 30xc2x0 C. being more particularly well suited.
In may be necessary to bring the crude reaction mixture resulting from Stage (a1) to this temperature before carrying out Stage (b1), in so far as the temperature conditions involved in Stages (a1) and (b1) differ.
More generally, a person skilled in the art may draw inspiration from the operating conditions described in the literature for the Wittig and Horner-Emmons reactions for the purpose of preparing the compound of formula (I) in which n is 1 and Y represents (C1-C5)alkoxy obtained on conclusion of Stages (a1) and (b1).
Stage (c1) makes possible the hydrolysis of the ester of formula (I) resulting from Stage (b1). This stage is advantageously carried out in basic medium. The bases generally used for the saponification of esters can be used for the implementation of Stage (c1). These bases preferably inorganic bases of the alkali metal hydroxide type (NaOH, KOH) or of the alkali metal carbonate type (K2CO3, Na2CO3).
The hydrolysis of the ester functional group is generally carried out in a solvent, such as a protic solvent. (C1-C5)alkanol [sic], water and their mixtures are particularly well suited.
The hydrolysis is advantageously carried out at a temperature of 0 to 100xc2x0 C., for example 20 to 80xc2x0 C., in a mixture of methanol and water, by reaction with sodium hydroxide.
The amount of base needed is usually between 1 to 5 equivalents with respect to the ester of formula (I), preferably between 1 and 2 equivalents.
Although this does not correspond to a preferred embodiment of the invention, the hydrolysis of the ester functional group can be carried out in acidic medium.
In order to determine the ideal conditions for hydrolysis of the ester functional group, a person skilled in the art should refer, for example, to Protective Groups in Organic Synthesis, Greene T. W. and Wuts P. G. M., published by John Wiley and Sons, 1991, and to Protecting Groups, Kocienski P. J., 1994, Georg Thieme Verlag.
Stage (d1) is carried out for the preparation of compounds of formula (I) in which Y represents xe2x80x94NRcRd.
In comprises a conventional reaction of the carboxylic acid obtained in Stage (c1) with an amine of formula NHRcRd. It is more particularly advantageous to react an activated form of the carboxylic acid of formula (I) with the amine NHRcRd. Such an activated form is, for example, a carboxylic acid anhydride, an acid chloride or a mixed anhydride. The amidation of the carboxyl functional group will be carried out in a way known per se by a person skilled in the art.
Process B makes possible the preparation of the compounds of formula (I) in which n=2. This process comprises the stages composed of:
(a2) preparing an ylide
xe2x80xa2either by reaction of a base with a phosphonate of formula (IVa): 
in which
Rxe2x80x2j and Rxe2x80x2k independently represent an Rxe2x80x2 group as defined in Claim 1 [sic];
T6 and T7 independently represent (C1-C5)alkyl; and
Y represents (C1-C5) alkoxy;
xe2x80xa2or by reaction of a base with a phosphonium salt of formula (IVb): 
in which
Rxe2x80x2j and Rxe2x80x2k independently represent and Rxe2x80x2 group as defined in Claim 1 [sic];
T8, T9 and T10 independently represent (C1-C5)alkyl or (C6-C10)aryl optionally substituted by (C1-C5)alkyl;
Y represents (C1-C5)alkoxy; and
hal represents a halogen atom;
(b2) reacting the ylide prepared in Stage (a2) with an aldehyde of formula: 
in which
R, p, X and A are as defined in Claim 1 [sic];
one and one alone of Rxe2x80x21 and Rxe2x80x22 represents xe2x80x94CHO and the other takes one of the meanings given in Claim 1 [sic] for R1 and R2, with the exception of the Z chain, so as to obtain a compound of formula I [sic] in which n represents 2 and Y represents (C1-C5)alkoxy;
(c2) if appropriate, converting the ester obtained in Stage (b2) above in acidic or basic medium into the corresponding carboxylic acid of formula (I) in which Y represents OH;
(d2) if appropriate, reacting the carboxylic acid functional group of the compound of formula (I) resulting from Stage (c2) with an amine of formula HNRcRin which Rc and Rd are as defined in Claim 1 [sic], optionally after activation of the carboxyl functional group, so as to prepare the corresponding compound of formula (I) in which Y represents xe2x80x94NRcR.
The general conditions for carrying out Stages (a1) to (d1) also apply in carrying out the above Stages (a2) to (d2).
The phosphonate (IIa) is prepared conventionally, for example by carrying out the Arbuzov reaction. More specifically, when T1 and T2 are identical, a phosphite (IX):
P(OT1)3xe2x80x83xe2x80x83(IX)
in which T1 has the meaning given above for the formula (IIa), is reacted with a halide (X): 
in which Rxe2x80x2 and Y are as defined above for the formula (IIa) and hal represents a halogen atom.
The same type of reaction results in the preparation of the phosphonate (IVa).
The phosphonium salts of formula (IIb) are easily prepared in a way known per se by the reaction of a phosphine (V): 
in which T3, T4 and T5 are as defined for the formula (IIb),
with a halide (VI): 
in which Rxe2x80x2, Y and hal are as defined above for the formula (IIb).
Likewise, the phosphonium salt of formula (IVb) is easily prepared by the reaction of the phosphine (VII) 
in which T8, T9 and T10 are as defined above for the formula (IVb), with the halide (VIII): 
in which hal, Rxe2x80x2j, Rxe2x80x2k and Y are as defined above for the formula (IVb). Reference may be made to the experimental conditions described by A. Zumbrunn et al. in Helv. Chim. Acta, 1985, 68, 1519.
The aldehydes of formula (III) are commercially available or are easily prepared from commercial products by employing one of the following processes.
Process C for the preparation of the aldehydes of formula (III): 
in which Rxe2x80x21 represents xe2x80x94CHO.
The reaction sequence of Process C is illustrated in Scheme 1.
Stage (i) makes possible the reductive alkylation of the ketone (XI). This reaction comprises the reaction of the ketone (XI) with an organometallic compound
CH3xe2x80x94M
in which M is xe2x80x94MG-hal (where hal is a halogen atom) or else M is Li. 
In Stage (i), the nature of the organometallic compound determines the operating conditions.
When the organometallic [sic] is a Grignard reagent, use is advantageously made of a solvent which can be diethyl ether, tetrahydrofuran, dioxane, benzene, toluene or the like. The reaction temperature is from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably xe2x88x9210xc2x0 C. to 70xc2x0 C.
Stage (ii) makes possible the dehydration of the compound of formula (XII). This dehydration can be obtained by the action of an organic or inorganic acid on the compound (XII).
Mention may be made, as example [sic] of acids, of hydrochloric acid, sulphuric acid, nitric acid, trifluoromethanesulphonic acid, acetic acid, trifluoroacetic acid, para-toluenesulphonic acid or p-nitrobenzoic acid.
The appropriate solvents for this reaction are those conventionally used in the art which are furthermore capable of dissolving the compounds of formula (XII). Preferred solvents are aromatic hydrocarbons, such as benzene and toluene.
In Stage (iii), the radical bromination of the compound of formula (XIII) is carried out. This reaction can be carried out conventionally by the action of a brominating agent, either by irradiation or under the action of heat, optionally in the presence of an initiator, such as a peroxide or an azo compound.
Brominating agents are, for example, bromine or N-bromosuccinimide.
Radical initiator examples are xcex1,xcex1xe2x80x2-azobisisobutyronitrile and tert-butyl peroxide. A particularly appropriate solvent is carbon tetrachloride.
Stage (iv) involves the reaction of hexamethylenetetramine with the compound (XIV) in a first stage and treatment with a mixture of acetic acid and hydrochloric acid in a second stage.
The molar ratio of hexamethylenetetramine to the compound (XIV) is preferably between 1 and 3, preferably between 1 and 2.
The temperature for reaction of hexamethylenetetramine with the compound (XIV) preferably varies between 20 and 120xc2x0 C., better still between 30 and 80xc2x0 C. The reaction is advantageously carried out in a solvent. Mention may be made, as appropriate solvent, of optionally halogenated aliphatic, aromatic or cycloaliphatic hydrocarbons, for example chloroform, carbon tetrachloride, tetrachloroethylene and chlorobenzene.
The following acidic treatment comprises the treatment, in a first step, of the resulting reaction mixture with an acetic acid solution at a temperature of 20 to 120xc2x0 C. preferably of 30 to 80xc2x0 C. In a second step, concentrated hydrochloric acid is added to the reaction mixture, which is maintained at a temperature of between 20 and 120xc2x0 C. preferably between 30 and 80xc2x0 C.
Process D for the preparation of the compounds of formula (III): 
in which Rxe2x80x22 is xe2x80x94CHO, A represents xe2x80x94CR3R4xe2x80x94 as defined above and X represents O.
According to this process, an aldehyde of formula (XV): 
in which R and p are as defined above for the formula (III), is reacted with a compound of formula (XVI): 
in which R3 and R4 are as defined above for the formula (II), in the presence of a strong base.
This reaction is stoichiometric. Nevertheless, it is preferable to carry out the reaction in the presence of a slight excess of the compound (XV), so that the molar ratio of the compound (XV) to the compound (XVI) generally varies from 1 to 1.5, better still from 1 to 1.3.
The base which can be used in this reaction is advantageously an inorganic base, such as, for example, NaOH, KOH, NaHCO3, Na2CO3, KHCO3 or K2CO3. According to a preferred embodiment of the invention, the base is K2CO3.
The amount of base which has to be used corresponds to the amount of compound (XV) involved. Thus, the molar ratio of the base to the compound (XV) is preferably between 1 and 1.2.
This reaction can be carried out in a solvent. The nature of the solvent depends on the base used and on the reactants present. When the base is K2CO3, ethers are preferred solvents and in particular dioxane, tetrahydrofuran or diethyl ether. When the reaction is carried out in the presence of a solvent, the concentration of the reactants in the reaction mixture is preferably maintained between 0.05 mol/l and 5 mol/l, better still between 0.08 mol/l and 1.2 mol/l. The reaction temperature is advantageously between 30 and 150xc2x0 C., better still between 50 and 120xc2x0 C., for example between 90 and 100xc2x0 C.
Process E for the preparation of an aldehyde (III) of formula: 
in which Rxe2x80x22 represents the xe2x80x94COH [sic] group.
The reaction sequence of Process E is illustrated in Scheme 2. 
Process E comprises the use of conventional reactions of organic chemistry. In Stage (i), the carboxylic acid (XVII) is esterified by an alcohol of formula RHOH in which RH is a (C1-C6)alkyl group.
The esterification is generally carried out in acidic medium. Catalytic amounts of acids of the paratoluenesulphonic acid type or sulphuric acid type are particularly appropriate. However, the reaction can be carried out in the presence of an excess of acid.
It is desirable to use a large excess of the alcohol RHxe2x80x94OH. Likewise, it is advantageous to introduce a dehydrating agent, such as molecular sieve, into the reaction mixture. A reaction temperature of between 20 and 120xc2x0 C., preferably between 50 and 100xc2x0 C., is ideal.
It is possible in many cases to use the alcohol RHxe2x80x94OH as solvent.
According to the invention, the nature of the RH group introduced in Stage (i) is not of any importance.
In the following stage, the ester (XVIII) is reduced to an alcohol (XIX). The reduction can be carried out according to any one of the methods known in the art.
Use may be made, as reducing agent, of, for example, lithium aluminium hydride, lithium borohydride, diisobutylaluminium hydride, lithium triethylborohydride, BH3-SMe2 at reflux in tetrahydrofuran, HSi(OEt)3 or even sodium borohydride.
In Stage (iii), the alcohol (XIX) is oxidized to an aldehyde, so as to obtain the expected aldehyde (XX). The oxidation is carried out in a way known per se. It is advisable to avoid the subsequent oxidation of the aldehyde to an acid. For this reason, the oxidizing agent will be suitably selected from MnO2, dimethyl sulphoxide, Collins""s reagent, Corey""s reagent, pyridinium dichromate, Ag2CO3 on celite, hot HNO3 in aqueous glyme, Pb(OAc)4-pyridine, ceric ammonium nitrate or N-methylmorpholine N-oxide.
Process F for the preparation of compounds of formula III [sic]: 
in which Rxe2x80x22 represents the xe2x80x94CHO group.
According to this process, the compounds of formula (III) are prepared by the reaction of a mixture of phosphorus oxychloride and dimethylformamide with a compound of formula (XXI): 
in which R, p, X, A and Rxe2x80x21 are as defined above for the formula (III).
Use is preferably made of a molar ratio of phosphorus oxychloride to the compound (XXI) and of a molar ratio of dimethylformamide to the compound of formula (XXI) varying between 1 and 3, better still between 1 and 2, for example between 1 and 1.5.
The dimethylformamide and the phosphorus oxychloride are advantageously used in equal amounts.
One way of carrying out the reaction comprises preparing a solution of the reactants, phosphorus oxychloride and dimethylformamide, in a solvent and then running a solution of the compound (XXI) into this solution.
The solution of the reactants is generally prepared by addition of phosphorus oxychloride to a solution of dimethylformamide in a solvent. A halogenated aliphatic hydrocarbon (such as dichloromethane) or acetonitrile can be chosen as appropriate solvent.
The addition of POCl3 to the DMF solution is preferably carried out under cold conditions, namely at a temperature of between xe2x88x9240 and 15xc2x0 C., advantageously between xe2x88x9210 and 10xc2x0 C., better still between xe2x88x925 and +5xc2x0 C.
The compound of formula (XXI) is added, preferably in solution in a solvent, to this solution. According to a preferred embodiment of the invention, the solvent is the same as that used to prepare the solution of the reactants.
The reaction of the compound (XXI) with the system of reactants DMF/POCl3 is carried out at a temperature of between 15 and 100xc2x0 C., preferably between 18 and 70xc2x0 C.
The compound of formula (XXI) is easily prepared from the corresponding ketone of formula (XI): 
in which R, p, X and A are as defined above for the formula (XXI). It is possible, for example, to prepare this compound by carrying out reactions analogous to those described above in the context of Process C (Scheme 1: Stages (i) and (ii)). Briefly, the above ketone (XI) can be reacted with an organometallic compound of formula: Rxe2x80x21-M, where M is a lithium atom or represents xe2x80x94MG-hal, hal being a halogen atom. The resulting compound of formula: 
in which R, p, X and A are as defined above, is then treated in acidic medium.
The ketones of formula (XL), the aldehydes of formula (XV) and the acids of formula (XVII) are commercial compounds or are easily prepared from commercially available products by employing conventional processes of the state of the art.
Another subject-matter of the invention is the new compounds of formula: 
in which:
A represents the bivalent radical xe2x80x94(CH2)sxe2x80x94CR3R4xe2x80x94(CH)2)txe2x80x94 where one of s and t represents 0 and the other 1;
R3, R4, R, p and X are as defined above for the formula (I); and
one alone of Rxe2x80x21 and Rxe2x80x22 represents xe2x80x94CHO, the other taking one of the meanings given above for R1 and R2 for the formula (I), with the exception of the Z chain.
Preference is given, among these compounds, to those in which Rxe2x80x21 represents xe2x80x94CHO.
Another group of preferred compounds is composed of the compounds of above formula (IIIa) in which
X represents O;
A represents xe2x80x94CH2xe2x80x94CR3R4xe2x80x94 in which the unsubstituted methylene group is bonded to X;
Rxe2x80x21 or Rxe2x80x22 represents H; (C1-C15)alkyl; (C1-C15) alkenyl [sic]; or phenyl optionally substituted by (C1-C5)alkyl, (C1-C5)alkoxy, a halogen atom or xe2x80x94CF3;
R3 takes any one of the meanings given above for Rxe2x80x21 or Rxe2x80x22 but does not represent xe2x80x94CHO;
R4 represents a hydrogen atom or (C1-C15)alkyl;
R is chosen from (C1-C9)alkoxy; phenyl; [sic] or phenylcarbonyl optionally substituted by a halogen atom, (C1-C5)alkyl, (C1-C5)alkoxy; [sic] xe2x80x94CF3 or xe2x80x94OCF3; a halogen atom; xe2x80x94CF3; and xe2x80x94OCF3; and
p is 0, 1 or 2.
Better still, preference is given to the compounds in which:
X represent O;
A represents xe2x80x94CH2xe2x80x94CR3R4xe2x80x94 in which the unsubstituted methylene group is bonded to X;
Rxe2x80x21 or Rxe2x80x22 represents a hydrogen atom;
R3 represents a hydrogen atom or a (C1-C5)alkyl group, such as methyl;
R4 represents (C1-C15)alkyl, preferably (C1-C5)alkyl, such as methyl;
R is chosen from a halogen atom, CF3, (C1-C5)alkoxy, phenyl and para-chlorobenzoyl;
p is 0, 1 or 2.
Mention may be made, as examples of such compounds, of:
3,3-dimethyl-5-formyl-7-bromo-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-9-methoxy-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7,8-dichloro-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7-fluoro-8-chloro-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7-(para-chlorobenzoyl-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7-trifluoromethyl-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7-fluoro-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7-chloro-2,3-dihydro-benzoxepine,
3,3-dimethyl-5-formyl-7,8-dimethoxy-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7-phenyl-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-2,3-dihydrobenzoxepine,
3,3-dimethyl-5-formyl-7-methoxy-2,3-dihydrobenzoxepine.
According to another of its aspects, the invention relates to the intermediate compounds of formula: 
in which:
A represents the bivalent radical xe2x80x94(CH2)sxe2x80x94CR3R4xe2x80x94(CH2)txe2x80x94 where one of s and t represents 0 and the other 1;
R3, R4, R, p and X are as defined above for the formula (I); and
Wo represents xe2x80x94CH3 or xe2x80x94CH2Br.
Preference is given, among these compounds, to those in which:
R3 represents H, (C1-C15)alkyl, (C1-C15)alkenyl [sic] or phenyl optionally substituted by (C1-C5)alkyl, (C1-C5)alkoxy, a halogen atom or xe2x80x94CF3;
R4 represents a hydrogen atom or (C1-C15) alkyl;
R is chosen from (C1-C9)alkyl; (C1-C5)alkoxy; phenyl; [sic] or phenylcarbonyl optionally substituted by a halogen atom, (C1-C5)alkyl, (C1-C5)alkoxy, xe2x80x94CF3 or xe2x80x94OCF3; a halogen atom; xe2x80x94CF3; and xe2x80x94OCF3; and
p is 0, 1 or 2.
Better still, the meanings of R3, R4, R and p will be chosen from the following groups:
R3 represents a hydrogen atom or a (C1-C5)alkyl group, such as methyl;
R4 represents (C1-C15)alkyl, preferably (C1-C5)alkyl, such as methyl;
R is chosen from a halogen atom, CF3, (C1-C5)alkoxy, phenyl and para-chlorobenzoyl;
p is 0, 1 or 2.
Examples of compounds in which Woxe2x80x94CH3 are represented in Table 4, which appears after the examples.
Mention may also be made of 3,3,5-trimethyl-7-methoxy-2,3-dihydrobenzoxepine.
Examples of compounds in which Wo=xe2x88x92CH2Br are represented in Table 5, which appears after the examples.
Mention may also be made of 3,3-dimethyl-5-bromomethyl-7methoxy-2,3-dihydrobenzoxepine.
The invention additionally relates to the intermediate compounds of formula (IIIb): 
in which:
Rxe2x80x21 represents a hydrogen atom, a (C1-C5)alkyl group or phenyl;
R3 and R4 are chosen independently from a hydrogen atom, a (C1-C18)alkyl group or a (C2-C18)alkenyl group.
Preference is given, among these compounds, to those in which Rxe2x80x21 represents a hydrogen atom.
Mention may be made, as examples of:
-2,2-dimethyl-3-formyl-2H-1-benzopyran;
-2-[non-3-enyl]-3-formyl-2H-1-benzopyran;
-2-undecyl-3-formyl-2H-1-benzopyran;
-2-pentyl-3-formyl-2H-1-benzopyran;
-2-nonyl-3-formyl-2H-1-benzopyran;
-4-methyl-3-formyl-2H-1-benzopyran; and
-4-phenyl-3-formyl-2H-1-benzopyran.
The invention additionally relates to pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of formula (I) as defined above in combination with one or more pharmaceutically acceptable vehicles.
These compositions can be administered orally in the form of immediate-release or controlled-release granules, hard gelatin capsules or tablets, intravenously in the form of an injectable solution, transdermally in the form of an adhesive transdermal device, or locally in the form of a solution, cream or gel.
A solid composition for oral administration is prepared by addition of a filler and, if appropriate, a binder, a disintegration agent, a lubricant, a colorant or a flavour enhancer to the active principle and by shaping or mixing as a tablet, a coated tablet, a granule, a powder or a capsule.
Examples of filters encompass lactose, maize starch, sucrose glucose, sorbitol, crystalline cellulose and silicon dioxide, and examples of binders encompass poly(vinyl alcohol), poly(vinyl ether), ethylcellulose, methycellulose [sic], acacia [sic], gum tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose [sic], calcium citrate, dextrin and pectin. Examples of lubricants encompass magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. The colorant can be any of those authorized for use in medicaments. Examples of flavour enhancers encompass cocoa powder, mint in herbal form, aromatic powder, mint in oil form, borneol and cinnamon powder. Of course, the table or the granule can be suitably coated with sugar, gelatin or the like.
An injectable form comprising the compound of the present invention as active principle is prepared, if appropriate, by mixing the said compound with a pH regulator, a buffer, a suspending agent, a solubilizing agent, a stabilizer, a tonicity agent and/or a preservative and by converting the mixture into a form for intravenous, subcutaneous or intramuscular injection, according to a conventional process. If appropriate, the injectable form obtained can be lyophilized by a conventional process.
Examples of suspending agents encompass methycellulose [sic], polysorbate 80, hydroxyethyl-cellulose, acacia [sic], gum tragacanth powder, sodium carboxymethylcellulose and polyethoxylated sorbitan monolaurate.
Examples of solubilizing agent [sic] encompass castor oil solidified with polyoxyethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate and the ethyl ester of castor oil fatty acid.
In addition, the stabilizer encompasses sodium sulphite, sodium metasulphite and ether, while the preservative encompasses methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenyl [sic], cresol and chlorocresol.
The invention is additionally targeted at the use of an active principle chosen from a compound of formula (I) as defined above in the preparation of a medicament intended to prevent or treat dyslipidaemias, atherosclerosis or diabetes.
The hypolipidaemic and hypoglycaemic activity of the compounds of the invention was demonstrated in vitro and in vivo by employing the following tests:
1) Demonstration of the in vitro activity.
The hypolipidaemic and hypoglycaemic effect of the compounds of the invention results from their ability to activate the PPARxcex1 and PPARxcex3 isoforms.
Analysis of the activation of PPARxcex1 and PPARxcex3 is based on the transfection of a DNA allowing the expression of a reporter gene (the gene of luciferase) under the control of the PPARs, either endogenous in the case of PPARxcex3 of exogenous in the case of PPARxcex1. The reporter plasmid J3TkLuc comprises three copies of the response element for PPARs of the human apo A-II gene (Staels, B et al. (1995), J. Clin. Invest., 95, 705-712) which are cloned upstream of the promoter of the thymidine kinase gene of the herpes simplex virus in the plasmid pGL3. This reporter gene was obtained by subcloning, in the plasmid pGL3, the plasmid J3TkCAT described above (Fajas, L et al. (1997), J. Biol. Chem., 272, 18779-18789). The cells used are green monkey CV1 cells transformed by the SV40 virus, which express PPARxcex3 (Forman, B. et al. (1995), Cell, 83, 803-812), and human SK-Hep1 cells, which do not express PPARs. These cells were inoculated at the rate of 20,000 cells per well (96-well plates) and transfected with 150 ng of reporter DNA complexed with a mixture of lipids. In the case of the SK-Hep1 cells, an expression vector for PPARxcex1, described by Sher, T. et al. (1993), Biochemistry, 32, 5598-5604, is cotransfected. After 5, hours, the cells are washed twice and incubated for 36 hours in the presence of the test compound in a fresh culture medium comprising 10% foetal calf serum. At the end of incubation, the cells are lysed and the luciferase activity is measured. This activity is expressed relative to the control value.
By way of example, the compound of Example 16b described below ((2E, 4E)-5-(3,3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid) increases, under these conditions, the luciferase signal by 300% in the CV1 cells and by 250% in the SK-Hep1 cells. In the presence of a pGL3 reporter vector devoid of a PPAR response element, the compound of Example 16b is inactive in both cell types.
2) Demonstration of the in vivo activity
The antidiabetic and hypolipidaemic activity of the compounds of formula I [sic] was determined by the oral route in db/db mice.
Two-month-old db/db mice are treated per os for 15 days with the compound of Example 16 (100 mg/kg/day). Each study group comprises seven animals. After treating for three days (D3) and fifteen days (D15), retro-orbital samples are taken after light anaesthesia and fasting for 4 hours.
The following measurements were taken:
quantitative determination of glycaemia (glucose oxidase) at D3 and D15 and of the lipid parameters with regard to the sera at D15 (COBAS): triglycerides, total cholesterol (CHOL), HDL cholesterol (HDL-C) and free fatty acids (FFA) (BioMxc3xa9rieux and Wako Chemicals quantitative determination kit).
The results obtained have been reported in the following table. The measurements which appear in this table are mean valuesxc2x1standard error.
These results unambiguously demonstrate the hypolipidaemic and antidiabetic activity of the compounds of the invention.
The following examples illustrate the invention without implied limitation.
The following abreviations have been used in the proton nuclear magnetic resonance (NMR) data: s for singlet, d for doubtlet, t for triplet, q for quartet, o for octet and m for mutiplet. The chemical shifts xcex4 are expressed in ppm; M.p. represents the melting point and B.p. the boiling point.